Drug abuse and addiction are major societal problems. Much of the previous research in this area has focused on understanding drug action at a cellular and molecular level. This research has helped to identify a basic neural circuit that appears to mediate reward-related processing. Key components of this system include brainstem dopamine neurons, the striatum, and orbitofrontal cortex. However, comparatively little research has focused on understanding, how these areas they interact with each other, and with other brain regions that are involved in non-affective cognitive processing. This is an important gap in our knowledge, since there are clear indications that interactions between affective and cognitive processes are critical components of drug abuse and addiction. Neuroimaging offers the opportunity to make important advances in this area, because it is a technique that allows activity changes in the reward-related circuitry to be monitored throughout the entire brain at once, and humans can be used as subjects. The overall objective of this research proposal is to use neuroimaging to advance our knowledge of how human behavior and brain function is influenced by rewards. Our work will be based upon an initial model of frontal-striatal interaction that is derived from previous research in animals and brain-damaged humans. We propose to evaluate our theoretical framework through a series of 6 inter-related sets of neuroimaging studies that will: 1) build bridges to previous animal research on the role of the striatum and brainstem dopamine neurons, 2) examine state and trait dependent differences in decision making and associated activity in ventral frontal cortex and the striatum, and 3) assess how this core circuitry involved in reward-related processing and decision-making influences cognitive task performance and patterns of functional brain activation in the domains of working memory and perceptual learning. The proposed research will advance our understanding of the brain regions that participate in reward-related processing, and it will demonstrate the relevance of a theoretical model derived mainly from prior research in animals for understanding human behavior. The enhanced understanding of the normal cognitive processes and neural systems involved in motivation and reinforcement provided by our work should be critical for efforts to understand how dysfunction of this same system can lead to drug abuse and addiction.